This application is a request for continuation of a K05 Senior Scientist Research and Mentorship Award for Dr. Kathryn A. Cunningham who is the Chauncey Leake Distinguished Professor of Pharmacology and Director of the Center for Addiction Research at the University of Texas Medical Branch at Galveston. My research goals for this K05 build from the compelling discovery that the serotonin (5-HT) 5-HT2A receptor (5-HT2AR) and 5-HT2CR play an excitatory and inhibitory role, respectively, in the control of behaviors assessed in animal models of stimulant addiction. We postulate that selective blockade of 5-HT2AR signaling, enhancement of 5-HT2CR signaling, or their combination would be therapeutically useful in stimulant addiction, however, there are no such ligands currently in clinical use. Appreciating that a greater comprehension of 5-HT2R neurobiology is necessary for us to make significant strides toward the development of 5-HT2R-based pharmacotherapeutic interventions for psychostimulant addiction, I will employ future K05 release time to learn the fundamentals of drug design, molecular modeling and structural biology, and apply my learning to the exploration of 5-HT2R protein complexes, modeling of protein pockets and interfaces, and the design of novel ligands for 5-HT2R signalosomes. Seven collaborators have agreed to provide their guidance in these chemical and biological perspectives. The central hypothesis of the K05 Research Plan is that selective disrupters of the interface between the 5-HT2CR and PTEN (protein phosphates and tensin homologue deleted on chromosome 10) will augment 5-HT2CR signaling and provide therapeutic efficacy to 'protect'against relapse. This recently-funded project integrates an expanded collaborative group to craft peptides or small molecules that inhibit the 5-HT2CR:PTEN association as a innovative pharmacological means to enhance 5-HT2CR function with an acceptable side effect profile. My mentoring goals are to actualize individualized and structured guidance for pre/postdoctoral fellows in my laboratory, and five junior faculty in the Center and to assure their lifelong commitment to addiction science and the search for effective diagnostics and therapeutics. My leadership goals are to build bridges among regional institutions to facilitate drug discovery and translational addiction science and to enrich mentoring across disciplinary boundaries. The perspectives, new chemical entities and fresh template to target protein: protein interactions will drive new concepts and directions in addiction and relapse therapeutics, and stimulate the environment to promote new conceptual thought in mentee career development. In addition, I will actualize my mentoring goals to improve the integration of chemical design, modeling and structural biology into the laboratory, particularly with our group's ability to understand this key literature and connect 5-HT2R protein structure with its functions in cellular and mammalian biological systems. PUBLIC HEALTH RELEVANCE: There is a fundamental gap in addiction treatment options, namely, the need for medications that effectively suppress relapse to stimulant dependence with a limited side effect profile. The present grant would provide the opportunity for the candidate to focus on research, mentoring and leadership goals with the ultimate intent to develop novel chemical probes with promise as new diagnostic and therapeutic modalities to combat stimulant abuse and addiction.